Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

View/ Open
Author
Rice, Gillian I
Jenkinson, Emma M
Forte, Gabriella MA
Anderson, Beverley H
Ariaudo, Giada
Bader-Meunier, Brigitte
Baildam, Eileen M
Battini, Roberta
Beresford, Michael W
Casarano, Manuela
Chouchane, Mondher
Cimaz, Rolando
Collins, Abigail E
Cordeiro, Nuno JV
Dale, Russell C
Davidson, Joyce E
De Waele, Liesbeth
Desguerre, Isabelle
Faivre, Laurence
Fazzi, Elisa
Isidor, Bertrand
Lagae, Lieven
Latchman, Andrew R
Lebon, Pierre
Li, Chumei
Livingston, John H
Lourenço, Charles M
Mancardi, Maria Margherita
Masurel-Paulet, Alice
McInnes, Iain B
Menezes, Manoj P
Mignot, Cyril
O’Sullivan, James
Orcesi, Simona
Picco, Paolo P
Riva, Enrica
Robinson, Robert A
Rodriguez, Diana
Salvatici, Elisabetta
Scott, Christiaan
Szybowska, Marta
Tolmie, John L
Vanderver, Adeline
Vanhulle, Catherine
Vieira, Jose Pedro
Webb, Kate
Whitney, Robyn N
Williams, Simon G
Wolfe, Lynne A
Zuberi, Sameer M
Crow, Yanick J
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1038/ng.2933Metadata
Show full item recordCitation
Rice, G. I., Y. del Toro Duany, E. M. Jenkinson, G. M. Forte, B. H. Anderson, G. Ariaudo, B. Bader-Meunier, et al. 2014. “Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.” Nature genetics 46 (5): 503-509. doi:10.1038/ng.2933. http://dx.doi.org/10.1038/ng.2933.Abstract
The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, and of other patients with undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004585/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:13454851
Collections
- HMS Scholarly Articles [17843]
Contact administrator regarding this item (to report mistakes or request changes)